Interpretive Summary: Cardiovascular diseases are multifactorial and blood lipids are one of their best characterized risk factors. In addition to blood cholesterol levels, triglycerides (TG) are also important risk factors and their levels are determined by genetic and environmental factors such as diet. Regarding the genetic component, a protein called APOA5 is one of the strongest regulators of blood TG concentrations; nevertheless, its mechanisms of action are poorly characterized. Genetic variability at the APOA5 gene has also been associated directly with increased cardiovascular disease risk; however, this predisposition could be attenuated in the context of a prudent diet. We have investigated in overweight/obese subjects (n= 1465) whether the interaction between a polymorphism at the APOA5 gene known as -1131T > C and dietary fat may modulate TG concentrations and body weight. Our results show a significant genotype-dietary fat interaction for obesity in such a way that those subjects with the genetic polymorphism at the APOA5 gene are protected from obesity even consuming a diet relatively high in fat. Therefore, these findings contribute to the development of more personalized dietary recommendations to achieve better obesity prevention.

Technical Abstract:
APOA5 is one of the strongest regulators of plasma TG concentrations; nevertheless, its mechanisms of action are poorly characterized. Genetic variability at the APOA5 locus has also been associated with increased cardiovascular disease risk; however, this predisposition could be attenuated in the context of a prudent diet as traditionally consumed in the Mediterranean countries. We have investigated the interaction between a single nucleotide polymorphism (SNP) at the APOA5 gene (-1131T . C) and dietary fat that may modulate TG-rich lipoprotein concentrations and anthropometric measures in overweight and obese participants. We recruited 1465 participants from a Spanish population (20–65 y old; BMI 25–40 kg/m2) attending outpatient obesity clinics. Consistent with previous reports, we found an association between the APOA5-1131T . C SNP and TG-rich lipoprotein concentrations that were higher in carriers of the minor allele than in noncarriers (P , 0.001). Moreover, we found a significant genotype-dietary fat interaction for obesity traits. Participants homozygous for the 21131T major allele had a positive association between fat intake and obesity, whereas in those carrying the APOA521131C minor allele, higher fat intakes were not associated with higher BMI. Likewise, we found genotype-dietary fat interactions for TG-rich lipoproteins (P , 0.001). In conclusion, we have replicated previous gene-diet interactions between APOA5 -1131T . C SNP and fat intake for obesity traits and detected a novel interaction for TG-rich lipoprotein concentrations. Our data support the hypothesis that the minor C-allele may protect those consuming a high-fat diet from obesity and elevated concentrations of TG-rich lipoproteins.